We propose to explore two novel metabotropic G-protein coupled receptors (GPCRs): one that is sensitive to sweet taste ligands and another that is activated by glycine. GPCRs represent a diverse family of proteins involved in neuronal function. The importance of GPCRs in retina is obvious because a pair of these receptors are responsible for phototransduction (rhodopsin) and for the formation of ON responses (mGluR6) throughout the visual pathway. Furthermore, two of the primary retinal neurotransmitters, GABA and glutamate, activate GPCRs throughout the neural retina. We found two taste receptor proteins in rat retina that are identical to those in the tongue. Unlike the tongue, a key third protein subunit is missing in retina. Surprisingly, the two subunits that are present are sufficient to detect sweet tastants, they detect some sweet tastants not detected in rat tongue, and they are more sensitive to sweet tastants than the tongue. We propose to test the hypothesis that retinal neurons possess a novel system that responds to extracellular glucose and that this system can influence synaptic transmission. Taste receptors may be important in normal retinal function and in diabetes. We have also recently found evidence for a metabotropic glycine receptor in retina. This is the first evidence that glycine activates metabotropic as well as ionotropic receptors. Since glycine is one of the three major neurotransmitter systems in retina, we will test the hypotheses that glycine regulates bipolar and amacrine cell outputs and acts in opposition to GABA activated metabotropic receptors. PUBLIC HEALTH RELEVANCE: This grant proposal will address the function of novel "sweet taste receptors" in retina. We hypothesize that these newly discovered receptors can influence how the normal retina functions and how that might change in diabetic conditions. We will also explore a new glycine receptor that controls inhibition in the retina.